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NSAIDs; (Non Steroidal Anti-Inflammatory Drugs); Types, Uses

NSAIDs (Nonsteroidal anti-inflammatory agents) are a group of medicines that relieve pain and fever and reduce inflammation. There are nearly two dozen different NSAIDs available, but they all work in the same way, and that is by blocking a specific group of enzymes called cyclo-oxygenase enzymes. Analgesics and adjunct pain medications share their mechanism of action. They all deliver analgesic effect by interfering with the pain signaling cascade.

Types of NSAIDs

Non-Narcotic Analgesics

Generic	Brand Name
Acetaminophen	Tylenol

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

Generic	Brand Name
Bromfenac	Prolensa, Bromday
Diclofenac	Cataflam, Voltaren, Zipsor
Diflunisal	Dolobid
Etodolac	Lodine, Lodine XL
Fenoprofen	Nalfon
Flurbiprofen	Ansaid
Ibuprofen	Advil, Cramp End, Dolgesic, Excedrin IB, Genpril, Haltran, Ibren, Ibu, Ibuprin, Ibuprohm, Ibu-Tab, Medipren, Midol IB, Motrin, Nuprin, Pamprin-IB, Q-Profen, Rufen, Trendar
Indomethacin	Indocin, Indocin SR, Tivorbex
Ketoprofen	Actron, Orudis, Oruvail
Ketorolac	Toradol, Sprix
Meclofenamate	Meclomen
Mefenamic Acid	Ponstel
Meloxicam	Mobic, Vivlodex
Nabumetone	Relafen
Naproxen	Aleve, Anaprox, Anaprox DS, EC-Naprosyn, Naprelan, Naprosyn
Nepafenac	Nevanac
Oxaprozin	Daypro
Phenylbutazone	Cotylbutazone
Piroxicam	Feldene
Sulindac	Clinoril
Tolmetin	Tolectin, Tolectin DS

Acetic acid derivatives & Oxicams

Aceclofenac Acemetacin Alclofenac Amfenac Bendazac Bromfenac Bumadizone Bufexamac Diclofenac Difenpiramide Etodolac Felbinac Fenclozic acid Fentiazac Indometacin Indometacin farnesil Isoxepac Ketorolac Lonazolac Oxametacin Prodolic acid Proglumetacin Sulindac Tiopinac Tolmetin Zomepirac^†
Oxicams	Ampiroxicam Droxicam Isoxicam Lornoxicam Meloxicam Piroxicam Tenoxicam

N-Arylanthranilic acids (fenamates) & Propionic acid derivatives
(profens)

Alminoprofen Benoxaprofen^† Carprofen^‡ Dexibuprofen Dexketoprofen Fenbufen Fenoprofen Flunoxaprofen Flurbiprofen Ibuprofen^# Ibuproxam Indoprofen^† Ketoprofen Loxoprofen Miroprofen Naproxen Oxaprozin Pirprofen Suprofen Tarenflurbil Tepoxalin^‡ Tiaprofenic acid Vedaprofen^‡ COX-inhibiting nitric oxide donator: Naproxcinod
N-Arylanthranilic acids (fenamates)	Azapropazone Clonixin Etofenamate Flufenamic acid Flunixin Meclofenamic acid Mefenamic acid Morniflumate Niflumic acid Tolfenamic acid Flutiazin
Coxibs	Apricoxib Celecoxib Cimicoxib^‡ Deracoxib^‡ Etoricoxib Firocoxib^‡ Lumiracoxib^† Mavacoxib^‡ Parecoxib Robenacoxib^‡ Rofecoxib^† Valdecoxib^†
Other	Aminopropionitrile Benzydamine Chondroitin sulfate Diacerein Fluproquazone Glucosamine Glycosaminoglycan Hyperforin Nabumetone Nimesulide Oxaceprol Proquazone Superoxide dismutase/Orgotein Tenidap

Narcotic Pain Medications (Painkillers)

Generic	Brand Name
Buprenorphine	Buprenex, Butrans transdermal patch
Butorphanol	Stadol
Codeine
Hydrocodone
Hydromorphone	Dilaudid, Dilaudid-5, Dilaudid-HP, Hydrostat IR, Exalgo ER
Levorphanol	Levo-Dromoran
Meperidine	Demerol
Methadone	Dolophine, Methadose
Morphine	Astramorph PF, AVINZA, Duramorph, Kadian, M S Contin, MSIR, Oramorph SR, Rescudose, Roxanol
Nalbuphine	Nubain
Oxycodone	OxyContin, Roxicodone, Oxecta
Oxymorphone	Numorphan
Pentazocine	Talwin
Propoxyphene	Cotanal-65, Darvon
Tapentadol	Nucynta

Central Analgesics

Generic	Brand Name
Tramadol	Ultram
Tramadol and Acetaminophen	Ultracet

Combinations

Generic	Brand Name
Butalbital, Acetaminophen, and Caffeine	Femcet, Fioricet, Esgic, Esgic-Plus
Butalbital, Aspirin, and Caffeine	Fiorinal
Butalbital, acetaminophen, caffeine, and codeine	Fioricet with Codeine
Hydrocodone and Ibuprofen	Hydrostal IR, Vicoprofen
Morphine/Naltrexone	Embeda
Oxycodone/Naltrexone	Troxyca ER
Pentazocine/Naloxone	Talwin NX
Narcotic Analgesics and Acetaminophen
Acetaminophen and Codeine	Capital with Codeine, Margesic #3, Phenaphen with Codeine, Tylenol with Codeine
Dihydrocodeine, Acetaminophen, and Caffeine	DHCplus
Hydrocodone and Acetaminophen	Allay, Anexsia 5/500, Anexsia 7.5/650, Dolacet, Dolagesic, Duocet, Hycomed, Hydrocet, Hydrogesic, HY-PHEN, Lorcet 10/650, Lorcet-HD, Lortab, Panacet 5/500, Panlor, Stagesic, T-Gesic, Ugesic, Vicodin, Zydone
Oxycodone and Acetaminophen	Endocet, Percocet, Roxicet, Roxilox, Tylox; Xartemis XR
Pentazocine and Acetaminophen	Talacen
Propoxyphene and Acetaminophen	Darvocet-N 50, Darvocet-N 100, E-Lor, Propacet 100
Narcotic Analgesics and Aspirin
Aspirin, Caffeine, and Dihydrocodeine	Synalgos-DC
Aspirin and Codeine	Empirin with Codeine
Hydrocodone and Aspirin	Damason-P, Lortab ASA, Panasal 5/500
Oxycodone and Aspirin	Endodan, Percodan, Percodan-Demi, Roxiprin
Pentazocine and Aspirin	Talwin Compound
Propoxyphene, Aspirin, and Caffeine	Darvon Compound-65, PC-Cap, Propoxyphene Compound-65

Topical Analgesics

Generic	Brand Name
Capsaicin	ArthriCare, ARTH-RX, Axsain, Capsagel, Dura-Patch, Methacin, Qutenza, Zotrix, Zotrix-HP

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Mechanism of Action of NSAIDs

Most NSAIDs act as nonselective inhibitors of the enzyme cyclooxygenase (COX), inhibiting both the cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) isoenzymes. This inhibition is competitively reversible (albeit at varying degrees of reversibility), as opposed to the mechanism of aspirin, which is irreversible inhibition. COX catalyzes the formation of prostaglandins and thromboxane from arachidonic acid (itself derived from the cellular phospholipid bilayer by phospholipase A₂). Prostaglandins act (among other things) as messenger molecules in the process of inflammation.

COX-1 is a constitutively expressed enzyme with a “house-keeping” role in regulating many normal physiological processes. One of these is in the stomach lining, where prostaglandins serve a protective role, preventing the stomach mucosa from being eroded by its own acid. COX-2 is an enzyme facultatively expressed in inflammation, and it is inhibition of COX-2 that produces the desirable effects of NSAIDs.When nonselective COX-1/COX-2 inhibitors (such as aspirin, ibuprofen, and naproxen) lower stomach prostaglandin levels, ulcers of the stomach or duodenum internal bleeding can result.

NSAIDs have been studied in various assays to understand how they affect each of these enzymes. While the assays reveal differences, unfortunately, different assays provide differing ratios. The discovery of COX-2 led to research to the development of selective COX-2 inhibiting drugs that do not cause gastric problems characteristic of older NSAIDs.

Paracetamol (acetaminophen) is not considered an NSAID because it has little anti-inflammatory activity. It treats pain mainly by blocking COX-2 mostly in the central nervous system, but not much in the rest of the body. However, many aspects of the mechanism of action of NSAIDs remain unexplained, and for this reason, further COX pathways are hypothesized. The COX-3pathway was believed to fill some of this gap but recent findings make it appear unlikely that it plays any significant role in humans and alternative explanation models are proposed.

NSAIDs interact with the endocannabinoid system and its endocannabinoids, as COX2 have been shown to utilize endocannabinoids as substrates, and may have a key role in both the therapeutic and adverse effects of NSAIDs, as well as in NSAIDs-induced placebo responses.NSAIDs are also used in the acute pain caused by gout because they inhibit urate crystal phagocytosis besides inhibition of prostaglandin synthase.

Indications/Uses of NSAIDs

NSAIDs are usually used for the treatment of acute or chronic conditions where pain and inflammation are present.

NSAIDs are generally used for the symptomatic relief of the following conditions.

Osteoarthritis
Rheumatoid arthritis
Mild-to-moderate pain due to inflammation and tissue injury
Low back pain
Inflammatory arthropathies (e.g., ankylosing spondylitis, psoriatic arthritis, reactive arthritis)
Tennis elbow
A headache
A migraine
Acute gout
Dysmenorrhoea (menstrual pain)
Metastatic bone pain
Postoperative pain
Muscle stiffness and pain due to Parkinson’s disease
Pyrexia (fever)
Ileus
Renal colic
Macular edema

Contra-Indications of NSAIDs

NSAIDs may be used with caution by people with the following conditions

Irritable bowel syndrome
Persons who are over age 50, and who have a family history of GI (gastrointestinal) problems
Persons who have had past GI problems from NSAID use

NSAIDs should usually be avoided by people with the following conditions

Peptic ulcer or stomach bleeding
Uncontrolled hypertension
Kidney disease
People that suffer from inflammatory bowel disease (Crohn’s disease or ulcerative colitis)
Past transient ischemic attack (excluding aspirin)
Past stroke (excluding aspirin)
Past myocardial infarction (excluding aspirin)
Coronary artery disease (excluding aspirin)
Undergoing coronary artery bypass surgery
Congestive heart failure (excluding low-dose aspirin)
In the third trimester of pregnancy
Persons who have undergone gastric bypass surgery
Persons who have a history of allergic or allergic-type NSAID hypersensitivity reactions, e.g. aspirin-induced asthma

The Side Effect of NSAIDs

NSAIDs’ common adverse effect profile.

Gastrointestinal toxicity	•Dyspepsia •Gastroduodenal ulcers •GI bleeding and perforation
Cardiovascular adverse effects	•Edema •Hypertension •Congestive heart failure •Myocardial infarction •Stroke and other Thrombotic events
Nephrotoxicity	•Electrolyte imbalance •Sodium retention •Edema •Reduce glomerular filtration rate •Nephrotic syndrome •Acute interstitial nephritis •Renal papillary necrosis •Chronic kidney disease [3]

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The most common

Confusion
Stomach pain,
Heartburn,
GI disorders (e.g. dyspepsia, abdominal pain, nausea, vomiting, diarrhoea, flatulence, constipation, malaena, haematemesis, ulcerative stomatitis, gastritis),indigestion,

Less common

Rare

Abdominal or stomach cramping, burning, or tenderness
back or leg pains
bleeding gums
blistering, peeling, or loosening of the skin
bloody or black, tarry stools
blue lips and fingernails
breast enlargement and tenderness
burning, crawling, itching, numbness, prickling, “pins and needles”, or tingling feelings
burning upper abdominal or stomach pain
chest pain, discomfort, or burning
confusion
continuing diarrhea
cough or hoarseness
coughing that sometimes produces a pink frothy sputum
cracks in the skin
dark urine
decreased appetite
decreased vision or any change in vision
depression
difficult or labored breathing
dizziness, faintness, or lightheadedness when getting up from a lying or sitting position
double vision
dry mouth
extreme fatigue
false sense of well-being
feeling of unreality
feeling of warmth
general body swelling
greatly decreased frequency of urination or amount of urine
hair loss
headache
heavier menstrual periods
increased hunger
increased sweating
jerky movements of the head, face, mouth, and neck
joint pain
large, flat, blue or purplish patches in the skin
large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
loss of appetite
loss of balance control
loss of bladder control
loss of consciousness
loss of hearing
loss of heat from the body
lower back or side pain
mask-like face
mood swings
muscle aches, pains, or weakness
muscle spasm or jerking of all extremities
numbness or tingling in the hands, feet, or lips
pain in the ankles or knees
pain or discomfort in the upper stomach or throat
pain with swallowing
painful or difficult urination
painful, red lumps under the skin, mostly on the legs
seeing, hearing, or feeling things that are not there
seizures
sense of detachment from self or body
severe constipation
severe mental changes
severe or continuing stomach pain
shuffling walk
skin rash, hives or welts, itching
slow, fast, irregular, pounding, or racing heartbeat or pulse
slowed movements
slurred speech
small red or purple spots on the skin
sore throat
unexplained weight loss
unpleasant breath odor
vaginal bleeding
vomiting of blood or material that looks like coffee grounds
weakness in the arms, hands, legs, or feet
weight gain
yellow eyes or skin

Symptoms of overdose

Confusion about identity, place, and time
severe headache
unusual drowsiness, dullness, or feeling of sluggishness

More common

Mild headache

Continuing ringing or buzzing or other unexplained noise in the ears
difficulty having a bowel movement (stool)
discouragement
feeling sad or empty
general feeling of discomfort or illness
hearing loss
irritability
loss of interest or pleasure
sleepiness
trouble with concentrating

Rare

Anxiety
bloated or full feeling
changes in patterns and rhythms of speech
excess air or gas in the stomach or intestines
feeling of constant movement of self or surroundings
involuntary muscle movements
lightheadedness
passing gas
sensation of spinning
tiredness
trouble sleeping
trouble with speaking

Drug Interactions of NSAIDs

NSAIDs may interact with following drugs, suppliments & may change the efficasy of drugs

aminoglycoside antibiotics (e.g., amikacin, gentamicin, tobramycin)
angiotensin converting enzyme inhibitors (ACEIs; e.g., captopril, enalapril, ramipril)
angiotensin receptor blockers (ARBs; e.g., candasartan, irbesartan, losartan)
beta-adrenergic blockers (e.g., metoprolol, atenolol)
calcium channel blockers (e.g., amlodipine, diltiazem, nifedipine, verapamil)
celecoxib
cilostazol
clopidogrel
corticosteroids (e.g., dexamethasone, hydrocortisone, prednisone)
cyclosporine
diuretics (water pills; e.g., furosemide, hydrochlorothiazide, triamterene)
5-ASA medications (e.g., mesalamine, sulfasalazine)
glucosamine
haloperidol
heparin
methotrexate
multivitamins
other non-steroidal anti-inflammatory medications (NSAIDs; e.g., diclofenac, ibuprofen, ketorolac, naproxen)
Omega-3 fatty acids
pentoxifylline
quinolone antibiotics (e.g., ciprofloxacin, norfloxacin, ofloxacin)
selective serotonin reuptake inhibitors (SSRIs; e.g., citalopram, duloxetine, fluoxetine, paroxetine, sertraline)
serotonin/norepinephrine reuptake inhibitors (SNRIs; e.g., desvenlafaxine, duloxetine, venlafaxine)
tricyclic antidepressants (e.g., amitriptyline, clomipramine, desipramine, trimipramine)
warfarin

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Drug interaction of NSAIDs and commonly used medications.

Medication	Interactions
Antiplatelets (aspirin, clopidogrel)	Increases risk of GI bleeding
Angiotensin-converting-enzyme inhibitor (ACEI) and Angiotensin Receptor Blockers (ARB)	Increases in blood pressure by attenuating antihypertensive effects
Beta-blockers	Increases in blood pressure by attenuating antihypertensive effects
Calcium antagonists	Increases in blood pressure by attenuating antihypertensive effects
Corticosteroids	Increases risk of GI bleeding
Digitalis glycosides	Increase serum digoxin level
Diuretics	Increases in blood pressure by attenuating antihypertensive effects
Methotrexate	NSAIDs reduce renal excretion of methotrexate, causing methotrexate toxicity.
Selective serotonin reuptake inhibitors (SSRIs)	Increases risk of GI bleeding
Warfarin and other anticoagulants	Increases risk of GI bleeding

The Food and Drug Administration expert advisory committee recommends that:¹⁰⁶

when COX-2 inhibitors and NSAIDs are to be used for the management of individual patients, they should be prescribed with the lowest effective dose and for the shortest duration.
they should not be prescribed for high-risk patients, e.g., patients with a history of ischemic heart disease, stroke or congestive heart failure, or in patients who have recently undergone CABG.
all prescription-strength NSAIDs will now display “black box” label warnings for the potential risk of cardiovascular and gastrointestinal adverse effects.
treatment with tNSAIDs alone in patients aged less than 65 years who do not have gastrointestinal risk factors is considered appropriate. Co-therapy with a PPI or treatment with a COX-2 inhibitor was considered unnecessary in these patients.
the use of a tNSAID alone was considered inappropriate in any patient with a previous gastrointestinal event and in those who concurrently receive aspirin, steroids or warfarin. These patients should receive either a tNSAID plus a PPI or a COX-2 inhibitor.
use of a COX-2 inhibitor with PPI co-therapy is appropriate only in patients at very high risk, such as those with a previous gastrointestinal event who are taking aspirin, and those who are taking aspirin plus steroids or warfarin.